Studies on the pathogenesis of drug-resistant herpes simplex virus infections in humans and development of a novel and rapid sensitivity assay system

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A life-long HSV-1 infections in a child with a congenital immunodeficiency syndrome, Wiskott-Aldrich syndrome(WAS), was closely observed virologically and clinically. The observation based on the virological analyses demonstrated that acyclovir(ACV), anti-HSV-1 drug-resistant HSV-1 infections emerged during the course of his life. Furthermore, it was revealed that virus thymidine kinase(vTK)-deficient and highly ACV-resistant HSV-1 could reactivate in humans, despite vTK-deficient HSV-1 was reported to be able to establish latency in neuronal ganglia, but not reactivate from latency. The vTK-deficient HSV-1 in the patient was revealed to reactivate from latency by the assistance of the vTK-positive and ACV-sensitive HSV-1 when it reactivated. An efficacious rapid antiviral sensitivity assay system was developed. The sensitivity of HSV-1 could be determined by measuring the inhibitory effect of ACV and other vTK-associated drugs on the replication of vTK-deficient HSV-1 in 293T cells expressed with recombinant vTK of the interest virus by transfection of the cells with mammalian cell expression vectors. The interest virus would be determined to be ACV-resistant if the inhibitory effect was significantly less than that in the cells expressed with wild? type vTK. The system can be applied not only to HSV-1, but also to varicella zoster virus.